Safety Assessment Procedures for Human Therapeutics☆

9.21

Safety Assessment Procedures for Human Therapeuticsq

SC Gad, Gad Consulting Services, Raleigh, NC, United States © 2018 Elsevier Ltd. All rights reserved.

9.21.1 Introduction 9.21.2 Investigational New Drug Application/Clinical Trials Application 9.21.3 New Drug Application 9.21.3.1 Proposed Product Labeling 9.21.3.2 Drug Classification 9.21.3.3 Chemistry, Manufacturing, and Controls (CMCs) 9.21.3.4 Nonclinical Pharmacology and Toxicology 9.21.3.5 Human Pharmacokinetics and Bioavailability 9.21.3.6 Clinical Data 9.21.3.7 Risk–Benefits Summary 9.21.4 Clinical Trials 9.21.4.1 Phase I 9.21.4.2 Phase II 9.21.4.3 Phase III 9.21.4.4 Phase IV 9.21.5 FDA Expedited Paths to Market Approval for Serious Conditions 9.21.6 “Alternate Path Development” 9.21.7 Postmarket Evaluation of Safety 9.21.8 Regulatory Approval and Commercial Distribution 9.21.9 Concluding Remarks References Further Reading Relevant Website

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Abbreviations (Q)SAR Quantitative structure activity relationships AERS Adverse event reporting system ALS Amyotrophic Lateral Sclerosis CMC Chemistry, manufacturing, and control CTA Clinical trials application CTD Common technical document FDA Food and drug administration GCP Good clinical practice ICH International conference on harmonization IND Investigational new drug application NDA New drug application NME New molecular entities

9.21.1

Introduction

Assessment of the potential safety of new therapeutic entities (NMEs) for use in humans is a long process which seeks to preclude (or at least limit) any adverse effects of such molecules in people. On aggregate, the system works quite well. This description of human clinical assessment procedures focuses on information gained from clinical trials. Because the pharmaceutical industry is so highly regulated, emphasis is placed on the role of procedures mandated by the International Conference q

Change History: June 2017. SC Gad made edits to the article and added new references. This is an update of RI Roth, Human Clinical Safety Assessment Procedures, Comprehensive Toxicology, Second Edition, edited by Charlene A. McQueen, Elsevier, Oxford, 2010, Volume 3, Pages 173–181.

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on Harmonization (ICH), and US Food and Drug Administration (FDA). Other developed countries have similar regulatory bodies which may have slight differences in their approach to the control of food and drug supplies. Regulation of drugs in the United States was preceded by earlier central governmental responsibility for assuring consumer safety of foods. In 1848, the first federal statute addressing drugs was passed when quinine was found to be adulterated. During the next 90 years, various laws were passed to assure the purity of food and drugs. In 1938, the Federal Food, Drug and Cosmetic Act was enacted. One of the key provisions of this act was the requirement that a new drug be proven safe before it could be distributed (thought there was no requirement to prove efficacy). During the next 25 years, the FDA’s role was more clearly defined and expanded by various amendments, acts, and court decisions. In 1962, as a result of the thalidomide tragedy in Western Europe (birth of thousands of malformed infants), the Kefauver–Harris Drug Amendments were passed. These amendments generally tightened the clearance procedures for new drugs to enhance assurances that new products were safe. For the first time, drug manufacturers were also required to prove to the FDA the effectiveness as well as the safety of their product. As a result of these activities, new molecular entities (NME) were now required to first establish potential clinical safety in nonclinical studies, then proceed through a prescribed series of investigational steps (“phases”) to demonstrate clinical safety and efficacy before these drugs could be approved for marketing. The two key milestones in the drug development and approval process constitute the beginning of human study and the ultimate submission of an application for marketing approval. Human testing is initiated after submission of an Investigational New Drug Application (IND) in the US or a Clinical Trials Application (CTA) in most other countries, then completion of human studies to generate data sufficient for product approval is marked by submission of a New Drug Application (NDA) or equivalent document. However, several other regulatory steps including meetings with FDA and regular (annual and otherwise) data submissions allow FDA and drug manufacturers to continuously monitor the developmental drug’s evolving safety profile. Prior to initial testing in humans, a drug’s toxicity profile can only be estimated, with suggestions of at-risk organ systems and drug-induced adverse effects coming from knowledge of other drugs in the class, if they exist, from computer modeling ((Q)SAR), and from in vitro and animal studies. Then, as the drug goes through a series of human investigations, a better understanding of the drug’s potential risks gradually develops. It should be noted that human testing of a drug prior to its marketing approval is necessarily limited by practical issues related to cost, time, and availability of patients. Characteristically, a new drug may be studied in anywhere from a few hundred to a few thousand human recipients (normal volunteers and patients) to establish its efficacy and safety. Subjects selected for human investigation of a new drug are chosen carefully based on well-defined inclusion and exclusion criteria so that results can be best interpreted minimizing the potential influence of confounders. As a result, the drug’s premarket safety assessment is often skewed from a more diverse, complicated population that is expected to be treated in real life once the drug is approved. In particular, patients with other diseases, preexisting organ dysfunctions, and special demographics (such as the elderly age group) may not be extensively exposed to the drug until after it achieves approval by FDA and/or other regulatory authority. As one would expect, the conclusion of a drug’s toxicity profile and general safety may change considerably once the drug is freely prescribed by doctors to a broader population of patients than the more limited group studied in the developmental program. Accordingly, ongoing clinical safety assessment in the postmarket phase (pharmacovigilance) is critical.

9.21.2

Investigational New Drug Application/Clinical Trials Application

IND and CTA applications are the documentation which allows a NME or new dosage form of an approved drug to proceed to clinical testing in humans. This documentation consists of preclinical evaluations that identify toxicities, pharmacologic data to suggest the NME has potential human benefits. This application also includes details of the chemical synthesis, the chemical structure, and in vitro and in vivo pharmacology. Required animal toxicology testing generates the data which, upon appropriate extrapolation and safety margins, support its likely safety at the initial selected dose for human testing. Requirements for content and format of the IND or CTA are discussed in FDA or other regional guidance. Animal toxicology data are critical for the initial assessment of a drug’s potential risks prior to its investigation in humans. Singledose and multiple-dose studies, typically in at least two animal species, identify organ systems at risk of toxicity. Additionally required are safety pharmacology studies and (usually) genetic toxicity testing. A large range of tested drug doses are employed to determine worst-case outcomes, identify possible toxicities that have a demonstrable dose dependency, and identify nontoxic doses so that, with appropriate mathematical safety factors applied, a presumed conservative maximal safe dose for human studies can be identified. The length of required dosing in the animal toxicology studies is based on the planned duration of dosing of patients in the clinical trials. Additional longer-term toxicology and reproductive studies usually are required before large-scale multicenter clinical trials are initiated. Ultimately, the point of the IND/CTA is to inform the regulatory authority that human testing is to be initiated, and give it the opportunity to provide feedback and, potentially, place a hold on human testing until there is a better understanding of the potential risks to subjects. In this way, the FDA or other authority can fulfill its mandate to provide oversight for the protection of human subjects, a responsibility which at this point of drug development is considered much more important than the question of whether the drug may work. Two common issues that arise with the beginning of human testing proposed in the IND/CTA are the identification of the initial to-be-tested dose level, and identification of any special safety testing that would need to be conducted to protect the human subjects. The initial dose level has to be determined to minimize toxicity on the basis of preclinical toxicology data – an IND does not have to be approved per se so it can be revised, and it can be “disapproved” or put on hold for good cause. FDA is required to conduct its review of

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the IND in a timely manner. Clinical testing may begin 30 days after filing, unless the IND is placed on hold and further information is required by the FDA. As one can imagine, it is not unusual for an IND to be put on hold for some time in the process. It is generally desirable for the drug’s sponsor to have a pre-IND meeting with the FDA (FDA), especially if any unusual metabolic, pharmacologic, or toxicologic data have been revealed in preclinical studies. Through the processes of submitting a pre-IND briefing document, which includes a series of carefully crafted questions that request FDA feedback and guidance on specific issues, it is generally possible to create a positive and useful initial dialog with the agency. Based on FDA’s input at the IND meeting on the posed questions, it is usually possible to craft an initial clinical study protocol that addresses all major potential safety issues. Such a meeting is also an opportunity to learn of any FDA safety concerns (or nonpublic knowledge of concerns about the class) that would need to be addressed by the clinical development program at stages beyond the first human study. A drug sponsor is required to submit an annual report to the FDA for every IND drug once “opened”, even if an active clinical trial is not underway. The annual report is a summary of all data reflecting the safety and effectiveness of the drug collected during the past year’s clinical testing. This report must also include summaries of any in vitro or in vivo toxicological studies that have been completed after the IND filing. Until a drug is approved by the FDA, the IND file contains the universe of important toxicity data for a drug, and is by definition a dynamic collection of relevant safety information.

9.21.3

New Drug Application

An NDA is the request for approval to market a therapeutic agent for the specified indication(s). The coordination of many disciplines is required to complete the NDA submission, and it must contain all relevant information needed for FDA’s deliberations of approvability. The format of NDA submissions has changed in recent years to a universal organization and presentation, the Common Technical Document (CTD), now used worldwide (FDA; Roth, 2008). Many sections of the Common Technical Document provide assessments of the drug’s clinical safety.

9.21.3.1

Proposed Product Labeling

The term product labeling technically includes all written or graphic information about the drug that accompanies prescription drugs. Of primary importance is the package insert, also known as the official package circular, prescribing information or professional labeling. The package insert provides healthcare professionals with information they need to prescribe drugs appropriately and provides patients with safety and other information they need to understand the drug, including risks that will be taken.

9.21.3.2

Drug Classification

Pharmacological and clinical data are included in this section which indicate the type of therapeutic activity of the NME. If a drug is part of a well-known pharmacologic class of therapeutic agents, its clinical safety profile can at times be anticipated to go beyond that demonstrated in the relatively limited extent of human exposure during the drug development program.

9.21.3.3

Chemistry, Manufacturing, and Controls (CMCs)

This section contains a description of the chemical synthesis and manufacturing processes, and a description of the quality control procedures and release specifications that are employed to ensure reliable, consistent safety (and efficacy) characteristics for the manufactured product.

9.21.3.4

Nonclinical Pharmacology and Toxicology

Nonclinical data (both positive and negative) that characterize systemic exposure and demonstrate the potential therapeutic benefits and safety of the NME are detailed in this section. Although animal toxicity does not always parallel human toxicity, the nonclinical safety assessment more often than not predicts toxicities that do not become recognized until large numbers of patients are treated after a drug’s approval. Nonclinical safety evaluation generally consists of three phases: (1) studies done to support NMEs going into clinical evaluation, (2) studies performed to support continued clinical development, and (finally), (3) studies performed to support marketing approval. The major components are systemic toxicity, genetic toxicity, safety pharmacology, reproductive and developmental toxicity, local tissue tolerance, and (eventually) carcinogenicity. Most potential NMEs are precluded from clinical evaluation in the first phase of nonclinical evaluation, the initial portion of which lasts for less than a year.

9.21.3.5

Human Pharmacokinetics and Bioavailability

Pertinent plasma drug level data, and sometimes drug data from other pertinent body fluids or tissues, are presented in this section, and the major routes of drug inactivation and elimination are identified. These data can impact the human safety assessment if it is demonstrated that the drug can potentially accumulate under a given dosing regimen, or if it is demonstrated that a pharmacokinetic/pharmacodynamic relationship exists for certain toxicities of clinical importance.

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9.21.3.6

Safety Assessment Procedures for Human Therapeutics

Clinical Data

A summary of available clinical data that demonstrate the therapeutic benefits and clinical safety of the NME must be provided. Safety data constitute the aggregate clinical assessment of toxicities and overall tolerability, including adverse experiences (side effects) seen in clinical trials, drug-induced changes in laboratory parameters, and identification of special toxicity findings that were observed during clinical investigation. Special safety-related findings of interest that are frequently highlighted are toxicities shown to be dose-related, toxicities of particular importance in demographic groups such as the pediatric or elderly populations, or in ethnic subgroups, and identification of any toxicities that might warrant special monitoring activities as a patient is given the drug. Examples of medical monitoring for specific potential toxicities include measurement of blood levels of the drug itself when it is known that the therapeutic window (difference between effective and maximum safe doses) is small, measurements of analytes specific for a specific target organ (e.g., liver function testing for a drug known to be hepatotoxic), or hearing testing for drugs known to be ototoxic.

9.21.3.7

Risk–Benefits Summary

This is a discussion of why the benefits exceed the risks under the conditions stated in the labeling. Even though a drug may have been demonstrated to have very substantial and clinically significant risks in the overall safety assessment, it may prove warranted to accept these toxicities given the potential efficacy of the drug, especially if use of other existing therapies or nontreatment are unacceptable alternatives. This discussion is generally in the form of an integrated safety and efficacy evaluation (ISS/ISE). In the decades since 1990 and prior to publication of this edition of Comprehensive Toxicology, a number (31 in the period from 1991 to 2013) of high profile drugs have been withdrawn from the market due to reasons of toxicity. Accordingly, FDA’s focus has increasingly been directed at a drug’s safety evaluation. Whereas evidence requirements for efficacy have seen some modulation with acceptance of surrogate endpoint data to gain approval (effectiveness conclusions to be confirmed later with definitive outcome data), evidence of safety has become an increasingly stringent requirement for approval. FDA review of many drugs today results in an “approvable” designation which demands, in many cases, additional information related to toxicities. As many new drugs demonstrate only marginal clinical benefit over existing marketed alternative products, the importance of safety has become one of both direct and relative importance.

9.21.4

Clinical Trials

Before beginning a discussion of the clinical development necessary for gaining regulatory approval, it is important to recognize that commercial success of a new drug, which depends on choices by formulary committees of a hospital, managed care organizations, or a government agency, often is predicated on safety profiles. Formulary decisions on drug selection are often driven by indirect costs of drug complications as much as direct cost of the drug itself. Clinical trials that include direct comparison with marketed products, especially those that are market leaders for a given indication, can provide relative safety data that impact not only approvability but also commercial viability. Before initiating the clinical trials that will be necessary for evaluation and approval by the FDA, a detailed development plan must be generated. This plan traditionally has included three major “phases” of human investigation prior to approval, plus the likelihood of additional studies conducted post-approval. A drug development plan includes not only studies to answer the question of whether the drugs work but also studies that acquire data for the proper clinical use of the NME, for example, information on the duration of safe dosing, dose adjustments that may be needed for special populations, or patient subgroups that may be particularly sensitive to toxicities. In some cases, a specific drug development plan made on the basis of nonclinical knowledge can be followed with minimal deviation. More commonly, though, safety results from one trial provide direction for the design of subsequent trials. Ultimately, the aggregate of data that constitute the human clinical safety assessment of one developmental drug may differ quite extensively from the data acquired for a different developmental drug. Therefore, it is not possible to provide a uniform description of safety assessments for each stage in the drug development process. Clinical evaluation proceeds in four phases: Phase I (clinical pharmacology and toxicity) trials establish safety and bioavailability and typically employ single doses in small numbers of normal volunteers; Phase II trials continue to evaluate safety but also attempt to establish efficacy and an appropriate dosage regimen in a limited population of selected patients; Phase III trials are full-scale evaluations of treatment in a large patient population using multicenter comparison of the NME with known treatments and, very commonly, comparison with placebo; Phase IV (postmarketing or post-approval) studies may be initiated after the drug has been approved for marketing, and are used for specific purposes such as to monitor possible adverse reactions or better define long-term efficacy. Although not all clinical trials have to be conducted in the United States, studies must be performed in conformance with good clinical practices (GCPs). As clinical experience with the NME increases and efficacy in humans becomes more certain (Phase II trials), additional development procedures have to occur. Additional toxicology studies (usually long-term toxicity, pharmacokinetics, carcinogenicity, and reproductive and developmental toxicity in two species) have to be initiated to support the longer and more diverse clinical trials; larger batches of drug have to be made to support these more elaborate toxicology and clinical testing programs, long-term stability of intended dosage formulations has to be determined, and Phase III plans have to be drawn up. Before Phase III clinical trials get underway an “end of Phase II” meeting is usually mandated by FDA. Results from all clinical trials, as well as from the animal pharmacology and toxicology studies, are reviewed. Plans or protocols for ongoing or additional

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toxicology studies and the proposed Phase III trials are discussed, and any deficiencies that may affect approval of the next step, the NDA, are pointed out to the sponsor. Upon completion of the Phase III clinical trials, all clinical results and all relevant support data, including manufacturing specifications, chemistry, nonclinical pharmacology and toxicology results, clinical indications and contraindications, package insert information, and promotion and advertising claims are collated and incorporated into an NDA. This NDA, which may consist of several hundred volumes, is then sent to FDA for approval. A year or more is typically required for initial FDA review and subsequent total approval time. Total cost of developing a drug from inception through approval, as commonly quoted in the literature at the time of publication of this edition, may exceed $800 million and 12 or more years of effort.

9.21.4.1

Phase I

Phase I trials are generally the first human exposure with an NME, and are planned to provide safety data with the least amount of risk to the human subjects. These trials are in most cases conducted in male volunteers who are disease-free, with the primary goal of achieving an extensive safety evaluation of the NME. However, if the drug is expected to be very toxic or is intended for serious indications such as cancer or ALS, it may not be ethical to introduce the compound into healthy volunteers. Phase I investigations are carried out with a full appreciation of the preclinical safety profile obtained from animal toxicology studies, and target organs of the NME’s toxicity identified in animal toxicology are carefully monitored in these early clinical trials. The subjects are usually under constant supervision which requires on-site housing to control diet and activity as well as round-the-clock monitoring. These initial clinical trials approach the full control achieved when dealing with test animals in toxicology studies. The rules of informed consent must be adhered to with meticulous care and the clinical investigators conducting the trials must be very experienced and conscientious. There are two general types of Phase I trials that are performed. The first type is the single-dose, dose-escalating study to provide an initial characterization of the drug’s safety and tolerability profile. The second type of Phase I trial evaluates the drug in multiple dosing protocols so that the tolerable dose range can be better defined. Endpoints that are anticipated from Phase I studies include identification of drug-induced side effects, definition of maximally tolerated doses and dose-limiting toxicities, and identification through laboratory analyses of organs at risk of toxicity. Dose evaluation in Phase I will characterize toxic effects of the drug with regard to severity and reversibility (resolution of the effect) to help define the dose range that will be evaluated in efficacy trials. Phase I trials also include those conducted to obtain pharmacokinetic data, including evaluation of the absorption, excretion, plasma clearance, and metabolic pathways of the NME in human subjects. Single-dose pharmacokinetic data provide the basis for choosing doses and dose intervals to include in later-phase trials. Multiple-dose pharmacokinetic data allow an evaluation of drug kinetics after steady state has been approached, and importantly (from the safety perspective) identify whether a given dosing regimen results in drug accumulation. Phase I trials that incorporate pharmacokinetic analysis can correlate administered doses with drug levels in blood that are associated with adverse effects of the NME. Safety evaluation in humans is the prime focus during Phase I, and remains of equivalent importance to efficacy determination throughout the various later phases of clinical development. A drug under development will be abandoned if the safety profile is unacceptable, and no matter how complete the nonclinical animal toxicology data may be it is impossible to predict which clinical safety problems may arise in man. Once later-phase studies are initiated in patients, there is an almost infinite combination of factors such as patient demographics, concurrent diseases, drug interactions, and genetic predisposition that can impact the safety evaluation of the NME. Because of this problem, investigators must always be alert to any negative safety signals uncovered during clinical development, no matter how weak or uncommon. Unusual or unanticipated clinical toxicity problems are common causes of delay in clinical trials, especially in those cases in which further exploration of the toxicity of interest is required in animal models before it is safe to reinitiate human investigations.

9.21.4.2

Phase II

Phase II clinical trials continue the safety evaluation of an NME and begin the clinical efficacy evaluation. These studies, usually small scale, are conducted in patients with the disease which the NME was designed to treat. Of particular importance to the clinical safety assessment of an NME, it is necessary for investigators to assign a likelihood that any given adverse event or laboratory abnormality encountered during dosing may (or may not) be related to the NME. Standard categories include unrelated, unlikely related, possibly related, and probably or definitely related. Many observed complications in trials involving sick patients are either manifestation of the underlying disease, concomitant illnesses, or concomitant medications, and it is important that clinical investigators in Phase II studies are experts in the disease states to be studied so that “relatedness” to the NME can be assessed. Phase II studies often employ a placebo-control design, unless deemed unethical, so that efficacy responses and any safety problems encountered can best be judged whether or not drug-related. Phase II investigations are designed to answer as many questions as possible concerning dose response and adverse effects in patients with the disease of interest. Some adverse effects may have a dose relationship such that dosing limits can be set for future studies. This is critical information to be obtained because FDA’s general principle is that recommended dosing of a drug should be the lowest effective dose that retains tolerability. Often in Phase II studies additional information will be obtained in the diseased patients concerning drug pharmacokinetics or potential drug interactions. An experienced and thorough team of well-trained clinical research investigators and staff must be intimately involved in the conduct of these trials in order to assure that complete and accurate safety (and efficacy) data are collected. For FDA to be able

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to conclude that clinical safety data are true, investigations must conform to GCPs and all results be verifiable from source materials. Each developed country has sets of GCP guidelines that must be followed. To produce the most interpretable data, it is common to keep the objectives of each study very well defined, and often fairly narrow. Rather than trying to answer several key questions with one study protocol, it is often better to have a separate protocol for each question. When conducting Phase II trials, data collection has to be as accurate as possible, especially with regard to monitoring for adverse events and laboratory abnormalities occurring during the course of the study. Particular emphasis is placed on any patients who die during the conduct of a study, have adverse consequences deemed serious (according to strict FDA definition) and clinically significant, or discontinue the medication. The accurate collection of data must be completely documented with an auditable paper trail and be as timely as possible, and safety signals explored to the fullest. In order to carefully evaluate each patient who is exposed to the test medication, frequent and thorough site visits by representatives of the drug sponsor must be completed. At the end of Phase II, careful evaluation of all safety and efficacy data are conducted. This stage of the investigational program represents one of the key “go/no go” decision points in the development of the NME. From this point on, the immense clinical costs of drug development escalate very rapidly. The project team meetings that will now be held should seek clear answers: Is the drug safe and effective? Should Phase II be expanded or terminated? What will be the design and objective of Phase III clinical trials? The project team may also require input from key investigators and consultants at this time in evaluating the future of the NME. An important FDA meeting (end of Phase II meeting) is scheduled at this point to discuss plans for the larger, multicenter Phase III clinical trials. It is usually wise to bring expert consultants and investigators to this meeting whose opinions may be viewed by regulatory agencies as less biased than company personnel.

9.21.4.3

Phase III

This phase of the clinical research program is intended to provide data in further support of the efficacy and safety conclusions from the Phase II trials. Phase III studies are larger than Phase II studies, and characteristically are designed to give the most unambiguous data (e.g., they are randomized, double-blinded, placebo controlled, and conducted in the intended patient population). Study designs that incorporate either placebo or active drug comparator arms provide an objective approach to the evaluation of observed safety findings. The large sizes of these studies allow determination of adverse event frequencies with some degree of certainty, especially those findings that are common. Large size also provides an opportunity to detect important but less common events; for example, a database of approximately 3000 treated patients would have reasonable likelihood of identifying drug complications occurring at a rate of one in 1000 patients. The more patients that are studied in Phase III, the better will be the understanding of how severe adverse experiences may be, and to what extent toxicities are reversible once the drug is discontinued. Large size of Phase III trials furthermore presents an opportunity to assess drug-related complications that may be either more common or more clinically significant in important patient subgroups defined by gender, age (general adult vs. pediatric vs. the elderly), race, or those with concomitant medical conditions such as preexisting renal or hepatic disease. Phase III trials characteristically are sufficiently long, and often incorporate relevant special testing, so that the range of event severity can be determined, and dispositions (reversibility) of adverse consequences can be known with some degree of certainty. If trials include a marketed drug active comparator arm, the safety assessment may be both direct and relative, providing comparative toxicity profiles that may ultimately become promotional arguments. Phase III trials generate the bulk of a drug’s clinical exposure that enables a physician prescribing a drug to understand the relative risks of the drug and to assess the benefit-to-risk ratio for his own particular patients. The majority, though not all, NME development programs consist of at least two Phase III trials as currently favored by FDA. Following completion of Phase III studies, a pre-NDA meeting is scheduled with FDA. This is an opportunity to learn whether critical gaps may exist in the development data and discuss filing issues, including whether previously identified issues with the overall safety assessment have been adequately addressed.

9.21.4.4

Phase IV

Phase IV trials consist of clinical research conducted after a drug has been approved. Due to the modest size of developmental drug programs, evaluation of a drug’s toxicity profile and overall understanding of its safety can only partially be determined prior to approval. The understanding at approval of an NME’s toxicity profile and overall benefit–risk is best considered provisional. FDA often imposes obligations on drug manufacturers, as a condition of FDA approval, to conduct one or more Phase IV postmarketing studies to fill important data gaps. Such gaps could be clinical experience in patient populations not adequately investigated previously (e.g., the geriatric age group), studies to more definitely quantify known risks and toxicities, and evaluation of potential drug interactions. Other common clinical studies that FDA requires but is often willing to leave for a Phase IV commitment are trials in the pediatric age group, and in hepatic or renally-impaired patients. In other instances, Phase IV studies, driven by promotional considerations, are intended to explore the use of the drug for new indications or in a broader range of patient groups. As an NME’s exposure profile expands into new patient subgroups, or new disease indications, new toxicity information relevant to the drug’s overall clinical safety assessment may ensue.

9.21.5

FDA Expedited Paths to Market Approval for Serious Conditions

In the last 15 years, several new pathways to market have been developed to facilitate prompt availability of NMEs for serious conditions for which no (or only inadequate) therapy exists.

Comparison of FDA’s expedited programs for serious conditions Breakthrough therapy

Accelerated approval

Priority review

Designation l Section 506(b) of the FD&C Act, as added by section 112 of the Food and Drug Administration Modernization Act of 1997 (FDAMA) and amended by section 901 of the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA) l A drug that is intended to treat a serious condition AND nonclinical or clinical data demonstrate the potential to address unmet medical need OR l A drug that has been designated as a qualified infectious disease producta

Designation l Section 506(a) of the FD&C Act, as added by section 902 of FDASIA

Approval pathway l 21 CFR part 314, subpart H l 21 CFR part 601, subpart E l Section 506© of the FD&C Act, as amended by section 901 of FDASIA

Designation l Prescription Drug User Fee Act of 199.

l

A drug that is intended to treat a serious condition AND preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies

l

When to submit request

l

l

With IND or after Ideally, no later than the end-of-phase 2 meeting

Timelines for FDA response Features

l

Nature of program Reference

Qualifying criteria

l

With IND or after Ideally, no later than the pre-BLA or pre-NDA meeting

Within 60 calendar days of receipt of the request l Actions to expedite development and review l Rolling review

l

l l l l l

Additional considerations

a

l

Designation may be rescinded if it no longer meets the qualifying criteria for fast tracke

l

Within 60 calendar days of receipt of the request Intensive guidance on efficient drug development Organizational commitment Rolling review Other actions to expedite review Designation may be rescinded if it no longer meets the qualifying criteria for breakthrough therapyf

l An application (original or efficacy A drug that treats a serious condition AND generally provides a meaningful advantage over supplement) for a drug that treats a serious available therapies AND demonstrates an effect condition AND, if approved, would provide on a surrogate endpoint that is reasonably likely a significant improvement in safety or to predict clinical benefit or on a clinical endpoint effectiveness OR that can be measured earlier than irreversible l Any supplement that proposes a labeling morbidity or mortality (IMM) that is reasonably change pursuant to a report on a pediatric likely to predict an effect on IMM or other clinical study under 505A ORb benefit (i.e., an intermediate clinical endpoint) l An application for a drug that has been designated as a qualified infectious disease productcOR l Any application or supplement for a drug submitted with a priority review voucherd l The sponsor should ordinarily discuss the l With original BLA, NDA, or efficacy possibility of accelerated approval with the supplement review division during development, supporting, for example, the use of the planned endpoint as a basis for approval and discussing the confirmatory trials, which should usually be already underway at the time of approval l Not specified l Within 60 calendar days of receipt of original BLA, NDA< or efficacy supplement l Approval based on an effect on a surrogate l Shorter clock for review of marketing endpoint or an intermediate clinical endpoint application (6 months compared with the 10that is reasonably likely to predict a drug’s month standard review)c clinical benefit l

l Designation will be assigned at the time of Promotional materials original BLA, NDA, or efficacy supplement Confirmatory trials to verify and describe the filing anticipated effect on IMM or other clinical benefit l Subject to expedited withdrawal l

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Title VIII of FDASIA, Generating Antibiotic Incentives Now (GAIN), provides incentives for the development of antibacterial and antifungal drugs for human use intended to treat serious and life threatening infections. Under GAIN, a drug may be designated as a qualified infectious disease product (QIDP) if it meets the criteria outlined in the statute. A drug that receives QIDP designation is eligible under the statute for fast track designation and priority review. However, QIDP designation is beyond the scope of this guidance. b Any supplement to an application under section 505 of the FD&C Act that proposes a labeling change pursuant to a report on a pediatric study under this section shall be considered a priority review supplement per section 505A of the FD&C Act as amended by section 5(b) of the Best Pharmaceuticals for Children Act. c See footnote a above. d Any application or supplement that is submitted with a priority review voucher will be assigned a priority review. Priority review vouchers will be granted to applicants of applications for drugs for the treatment or prevention of certain tropical diseases, as defined in section 524(a)(3) and (a)(4) of the FD&C Act and for treatment of rare pediatric diseases as defined in section 529(a)(3) of the FD&C Act. e A sponsor may also withdraw fast track designation if the designation is no longer supported by emerging data or the drug development program is no longer being pursued (see section A.5. of Appendix 1). f A sponsor may also withdraw breakthrough therapy designation if the designation is no longer supported by emerging data or the drug development program is no longer being pursued (see section B.5. of Appendix 1). Extracted from FDA (2014).

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Fast track

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9.21.6

Safety Assessment Procedures for Human Therapeutics

“Alternate Path Development”

Alternate path development comprises “compassionate use” or “expanded access” programs. These noncontrolled trials allow for the distribution of a not-yet approved NME to extremely sick, often terminally ill, patients who may be without other therapeutic options. Essentially humanitarian in function, these trials allow the treatment of very complex patients who have not been preselected according to strict inclusion and exclusion criteria that often produces a relatively narrowly defined group of investigational subject in Phase I–IV trials. Existing clinical safety data may be relatively scant when patients first receive an NME according to such programs, and the distinction between safe and unsafe doses may not yet have been determined. As may be expected with such patient populations, many clinical complications can arise during treatment, and interpretation of the safety data may be difficult due to a myriad of confounding processes. In general, the utility of such information to augment an NME’s clinical safety assessment may be extremely limited.

9.21.7

Postmarket Evaluation of Safety

At the end of Phase III in the development program of an NME, the NDA is ready to be prepared for submission. After what may have been up to 10 or even more years of clinical investigation, patients exposed to the NME at the time of FDA approval generally number in the hundreds to low thousands. Accordingly, the clinical safety assessment at the time of approval is relatively limited. Although variables such as the number of eligible patients, aggressiveness of marketing, and competition from existing marketed drugs for the indication will all influence the rate at which additional patients are exposed to the newly approved NME in real life, it is not uncommon that human exposures to an NME will exceed within weeks of market approval the aggregate exposure during years of clinical development. FDA attempts to capture cumulative real-world safety data from this post-approval blossoming of patient exposure by regulatory requirements for postmarket drug safety surveillance. Drug manufacturers are required to submit “expedited” reports of important safety information within short periods of time after learning of the finding of interest, and also are required to submit annual and periodic safety update reports. Those adverse experiences that qualify as serious and unexpected are readily available to the public through FDA’s computerized Adverse Event Reporting System (AERS) program and equivalent safety databases worldwide. By maintaining a steadily updated and expanded dataset of safety information on a marketed drug, manufacturers and FDA are able to continuously reevaluate the drug’s overall safety assessment. Almost invariably, unexpected safety findings come to light after a drug has been approved for marketing to patients. If new information is sufficiently worrisome or clinically important, it may prove necessary for manufacturers to modify the product labeling as provided to physicians and patients; in extreme cases, safety warnings are highlighted as a “Black Box Warning.” Sometimes new safety signals detected by the process of postmarket surveillance may require further clinical studies, and such information may require a reassessment of the risk–benefit ratio for the drug. Ultimately, a revision of the package insert may be required to convey new important safety information to prescribing physicians and patients. Only rarely are new postmarket findings of such clinical importance that drugs are removed (voluntarily or involuntarily) from the market.

9.21.8

Regulatory Approval and Commercial Distribution

To this point as much as 10 years of testing may have been consumed. To gain FDA approval of a new drug, numerous patients will have been studied as thoroughly as possible. The resulting clinical data package, as presented in the NDA, must convince the FDA and its advisory committees that this NME is safe and effective. If these qualities are met FDA will likely approve the new product. Commercial success, however, often rests with how the new drug compares with existing treatments for the clinical indication. If the new drug is relatively well tolerated compared to existing therapeutic options, and if serious toxicities are avoided, there is a good chance that prescribing physicians and patients will favor the new product. The developing experience with the drug by practicing physicians, as described at meetings and in publications, becomes a pivotal source for a drug’s ongoing safety assessment, especially once sponsor clinical trials are no longer being conducted.

9.21.9

Concluding Remarks

Since the time that federal regulation of drugs was first initiated there has been a guiding principle that a drug be safe, or at least that its toxicity risks be known, quantified, and fully acknowledged. Extensive testing in animals provides a head start in the drug safety assessment, often identifying mechanisms of toxicity that could also prove important in man. Human testing does not proceed until animal testing has identified potential toxicities and determined a likely safe dose. An NME is administered initially in low doses and in healthy human volunteers to ensure the lowest risk that investigational subjects might be harmed and identify adverse drug effects with the greatest certainty. Later stage trials involving patients bring the clinical safety assessment closer to real life, and provide some extent of quantitation of risk frequencies and severities. Consistent, comprehensive evaluation of toxicity is integral to all phases of human investigation with the NME, although the challenge of linking an observed safety-related abnormality to the investigational drug becomes much more difficult when studies

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are conducted in sick patients rather than healthy volunteers. Evaluation of drug toxicity then continues throughout the life of the marketed product with the goals of refining the understanding of common risks and identifying important new risks that may only become apparent after very large numbers of patients have been treated. Whereas drug efficacy testing often slows or even stops after an NME’s approval, drug safety assessments remain an important regulatory focus indefinitely.

References FDA (2014) Guidance for Industry: Expedited Programs for Serious ConditionsdDrugs and Biologics. Accessible at: http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugsgen/documents/document/ucm358301.pdf Last accessed 27th March, 2015. Roth, R. I. (2008). Drug Information Journal, 42, 149–159.

Further Reading Food and Drug Administration. Draft Guidance for Industry: Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including WellCharacterized, Therapeutic, Biotechnology-derived Products. Food and Drug Administration. Draft Guidance for Industry: Formal Meetings with Sponsors and Applicants for PDUFA Products. Food and Drug Administration. Draft Guidance for Industry: Submitting Marketing Applications According to the ICH/CTD Format: General Considerations. Spilker, B (Ed.). (1991). Terminology. In: Guide to Clinical Trials, p. xxii. Philadelphia: Lippincott Williams & Wilkins.

Relevant Website U.S. Food and Drug Administrationdhttp://www.fda.gov. http://www.phrma.org.